The pancreatic beta cell is the sole producer of physiologic levels of insulin. Type 2 diabetes develops when the pancreatic beta cell fails in the setting of increased insulin resistance. No current diabetes medication prevents beta cell failure. We propose that further understanding the pathways that control normal beta cell function will allow the more rational design of diabetes therapies that can prevent beta cell failure. To that end, we performed a whole genome RNA interference screen and identified Spry2 as a novel regulator of insulin production. Intriguingly, a single nucleotide polymorphism (SNP) near Spry2 is associated with type 2 diabetes, suggesting that it plays a role in diabetes pathogenesis. We generated a systemic genetic interaction map between top regulators of insulin transcription to understand how Spry2 might function. This map predicts that Spry2 may interact with Wfs1, a gene known to cause human diabetes via activation of the unfolded protein response (UPR). Indeed, we show that Spry2 is regulated by and regulates the UPR. The overall objective of this proposal is to define the role and mechanism of Spry2 in beta cell function, the UPR, and human diabetes. Specifically, we hypothesize that Spry2 is important for beta cell function and the UPR through an interaction with Wfs1. Our specific aims are: Aim 1: Demonstrate a role for Spry2 in beta cell function in vivo. We will characterize a beta cell specific knockout of Spry2. Aim 2: Elucidate the mechanism of Spry2 action on the UPR. We will test the functional importance of a Wfs1/Spry2 interaction and map the sites of Spry2 that are required for its modulation of the UPR. Aim 3: Test the function of Spry2 in human islets and identify the causative SNP near Spry2 that controls Spry2 expression. In the first part of the aim we will reduce Spry2 expression in human islets and measure insulin production, secretion and the unfolded protein response. In the second part of the aim, we will use genome editing to test potential causative type 2 diabetes SNPs for their ability to modulate Spry2 expression. The contribution of this proposal is the establishment of Spry2 as a new player in the beta cell UPR and in the pathogenesis of type 2 diabetes.